Administrative Supplement to 7R01HL148060-03 Titled: Opposing Effects of Prostaglandin E2 EP3 and EP4 Receptors on Mitochondrial

7R01HL148060-03 的行政补充，标题为：前列腺素 E2 EP3 和 EP4 受体对线粒体的相反作用

基本信息

批准号：
10711712
负责人：
PAMELA HARDING
金额：
$ 7.7万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2024-01-31
项目状态：
已结题

项目摘要

ABSTRACT Heart disease and heart failure are important causes of morbidity and mortality, affecting approximately 300 million people, at an enormous cost. Although current treatments slow the progression of these diseases, there has been little progress in preventing the compensated heart transitioning to that of a failing one. The Prostaglandin E2 (PGE2) receptor subtypes EP3 and EP4 are most abundant in the heart and activate different signaling pathways (Gαi for EP3, Gαs for EP4). Compelling data from my laboratory shows that EP3 expression is increased in the pathologically diseased heart produced by myocardial infarction (MI) or Angiotensin II- dependent hypertension (Ang II-HTN), that stimulation of the EP3 receptor decreases cardiac contractility whereas EP4 increases it and that overexpression of EP4 in the failing heart improves cardiac function. The failing heart switches from fatty acid (FA) oxidation to reliance on glucose. Coupled with this are alterations in mitochondrial function. Thus, mitochondrial dysfunction is an important player in the pathogenesis of heart failure. Our previous gene array data showed dramatic down regulation of mitochondrial genes in mice in which the EP4 receptor was deleted in cardiomyocytes; allowing PGE2 to act via the EP3 receptor and new data shows that an EP3 agonist reduces Complex I activity and ATP levels in adult mouse cardiomyocytes. mRNAs for proteins that alter both FA oxidation and their transport into mitochondria; specifically, carnitine palmitoyl transferase (CPT) were also down regulated in EP4 KO hearts. In other tissues, CPT activity was reportedly regulated by the transcription factor/orphan receptor NR4A2 (Nurr1) in a PGE2-dependent process but whether this occurs in the heart is unstudied. Since heart failure is characterized by reduced FA oxidation, we propose the novel overall hypothesis: EP3 is increased during cardiac injury and impairs mitochondrial function due to reduced fatty acid import via diminished CPT activity. This is mediated by decreased activity of the transcription factor, NR4A2. Ultimately these events contribute to heart failure. To test this hypothesis, we propose 3 aims that will use a new conditional and cardiomyocyte-specific EP3 KO mouse model coupled with an EP3 overexpressing transgenic mouse to determine whether upregulation of cardiomyocyte EP3 contributes to impaired contractile function and reduced mitochondrial function in heart failure caused by Ang II-HTN and MI. The study also examines whether PGE2 via its EP3 receptor reduces import of fatty acids into mitochondria via decreased activity of the transcription factor NR4A2 which subsequently reduces CPT activity; and whether these events reduce subsequent ATP levels. The proposal employs a multidisciplinary approach including physiological, biochemical and imaging studies that will impact the treatment of heart failure.

抽象的心脏病和心力衰竭是发病率和死亡率的重要原因，影响约300 百万人，巨额费用。尽管目前的治疗降低了这些疾病的进展，但防止完整的心脏过渡到失败的心脏方面几乎没有进步。前列腺素E2（PGE2）受体亚型EP3和EP4在心脏中最丰富，并激活不同信号通路（EP3的GαI，EP4的GαS）。我实验室的引人入胜的数据表明EP3表达在心肌梗塞（MI）或血管紧张素II-产生的病理疾病心脏中增加了依赖性高血压（ANG II-HTN），刺激EP3受体可降低心脏收缩力尽管EP4增加了IT，并且EP4在衰竭心脏中的过表达可改善心脏功能。这心脏失败从脂肪酸（FA）氧化转向葡萄糖的缓解。加上这是改变线粒体功能。这是线粒体功能障碍是心脏发病机理的重要参与者失败。我们以前的基因阵列数据显示了小鼠中线粒体基因的显着下调，其中 EP4受体在心肌细胞中被删除；允许PGE2通过EP3受体和新数据作用表明EP3激动剂降低了成年小鼠心肌细胞中的复合物I活性和ATP水平。 mrnas 对于改变FA氧化及其转运到线粒体的蛋白质；具体而言，肉碱巴尔线托在EP4 KO心脏中也调节转移酶（CPT）。据报道，在其他时候，CPT活动是受PGE2依赖性过程中的转录因子/孤儿受体NR4A2（NURR1）调节这发生在心脏中。由于心力衰竭的特征是FA氧化降低，因此我们提出了新的总体假设：心脏损伤期间EP3增加，并损害由于通过减少的CPT活性导入脂肪酸的降低。这是通过改善转录活性介导的因子，NR4A2。最终，这些事件导致心力衰竭。为了检验这一假设，我们提出了3个目标它将使用新的条件和心肌细胞特异性EP3 KO小鼠模型与EP3结合过表达的转基因小鼠，以确定心肌细胞EP3的上调是否有助于 ANG II-HTN和MI引起的心力衰竭的收缩功能受损并降低了线粒体功能。该研究还检查了PGE2是否通过其EP3受体降低了脂肪酸的进口到线粒体中通过降低转录因子NR4A2的活性，随后降低了CPT活性；是否这些事件降低了随后的ATP水平。提案员工一种多学科的方法，包括生理，生化和成像研究将影响心力衰竭的治疗。